One of the challenges for the successful commercialization of therapeutic proteins is to maintain the safety and efficacy of the protein during the manufacturing process, storage, and administration. To achieve this, the purified form of the protein drug is usually "formulated" with carefully selected excipients. The operations that occur subsequent to protein purification, such as freezing of the purified protein bulk, thawing of the bulk, formulation (excipient addition), sterile filtration, filling, freeze-drying, and inspection are commonly referred as "formulation and fill-finish operations". This review is focused on the protein formulation and fill-finish operations, critical process parameters at each operation, and the process considerations required for maintaining safety and efficacy of the drug during manufacturing and storage. Since proteins have complex molecular structures that can influence the protein stability, the reader is first introduced to salient concepts related to protein structure. This is followed by a review of the possible protein-degradation mechanisms and how a variety of external factors can contribute to protein degradation during the in vitro processing of the protein drug. The reader is then introduced to each of the formulation and fill-finish operations mentioned above, the possible degradations during each unit-operation, and process considerations necessary to avoid those degradations.